Abstract
The sliding filament theory and the cross-bridge model have been fundamental in understanding muscle contraction. While the cross-bridge model explains the interaction between a single myosin head and actin filament, the native myosin molecule consists of two heads. This review explores the possibility and mechanism of two-headed binding in myosin II to the actin. Recent studies using electron tomography and resonance energy transfer have provided evidence in support of the occurrence of two-headed binding. The flexibility of the regulatory light chain (RLC) appears to play a significant role in enabling this binding mode. However, high-resolution structures of the RLCs in the two-headed bound state have not yet been reported. Resolving these structures, possibly through sub-tomogram averaging or single-particle analysis, would provide definitive proof of the conformational flexibility of RLCs and their role in facilitating two-headed binding. Further investigations are also required to address questions such as the predominance of two-headed versus single-headed binding and the influence of the state of each of the heads on the other. An understanding of the mechanism of two-headed binding is crucial for developing a comprehensive model of the cross-bridge cycle of the native myosin molecule.